Evaluation of mechanistic role of artemin/GFRα3 signaling in osteoarthritis pain

artemin/GFRα3 信号在骨关节炎疼痛中的机制作用评估

基本信息

批准号：
10444070
负责人：
Duncan Lascelles
金额：
$ 66.79万
依托单位：
NORTH CAROLINA STATE UNIVERSITY RALEIGH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-01 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10444070
关键词：
Activities of Daily Living Address Adult Affect Afferent Neurons American Animal Model Arthralgia Arthritis Automobile Driving Behavioral Behavioral Assay Binding Biological Products Body Weight decreased Canis familiaris Chronic Complex Data Degenerative polyarthritis Development Discipline Disease Distant Economic Burden Enzyme-Linked Immunosorbent Assay Evaluation Exercise Family Felis catus Generations Hemorrhage Human Hypersensitivity Imaging Techniques In Vitro Incidence Individual Injections Injury Iodoacetates Joints Knockout Mice Lead Life Expectancy Link Measures Medial meniscus structure Mediating Modeling Molecular Monoclonal Antibodies Mus Myocardial Infarction Nerve Neural Pathways Neuronal Plasticity Neurons Non-Steroidal Anti-Inflammatory Agents Obesity Operative Surgical Procedures Opioid Outcome Measure Overdose Pain Pain management Pathway interactions Patients Persistent pain Persons Pharmacotherapy Proteins Proto-Oncogenes Quantitative Reverse Transcriptase PCR Receptor Protein-Tyrosine Kinases Reflex action Research Risk Role Signal Transduction Societies Solid Source Steroids Stroke Synovial Membrane TRP channel Testing Therapeutic Tissues Transgenic Mice Up-Regulation Weight maintenance regimen Work addiction afferent nerve base central pain chronic pain clinically relevant disability gastrointestinal glial cell-line derived neurotrophic factor inhibitor irritation joint destruction molecular imaging motor impairment mouse model neuromechanism neurotrophic factor new therapeutic target novel opioid overdose opioid use osteoarthritis pain pain relief pain sensitivity receptor response to injury side effect therapeutic target therapeutically effective tissue degeneration

项目摘要

PROJECT SUMMARY Arthritis affects almost 60M adult Americans and is increasing in incidence, with osteoarthritis (OA) being the most common form of arthritis. OA occurs due to degeneration of tissues comprising joints, and is associated with pain. OA pain is a major contributor to the burden of chronic pain in society. About 80% of persons with OA suffer movement limitations, and 25% cannot perform major activities of daily living. Current treatment options are limited to steroid injections, nonsteroidal anti-inflammatory drugs (NSAIDS), opioids and non- pharmacological approaches (exercise, weight loss). Unfortunately, each of these therapeutic approaches are problematic. Exercise, which helps weight management, is difficult for patients due to ongoing pain. NSAIDS can cause gastrointestinal irritation and bleeding and increase risk of heart attack or stroke, and opioids are associated with addiction and abuse (and can actually worsen chronic pain). Clearly, there is a critical need to identify new therapeutic targets and/or treatments for individuals suffering from OA pain. Here, we propose that a heretofore unrecognized neural pathway is a critical component of OA pain. This pathway involves ARTN, its receptor GFRα3, and ‘pain’ channels on nerves (transient receptor potential [TRP] channels). Activation of this pathway initiates and maintains OA pain. The central hypothesis (based on preliminary data in multiple species [mouse, dog, cat, human]) is that ARTN, released from synovium of the OA joint in response to injury, results in de novo increase in its receptor, GFRα3, in local and distant sensory nerves, producing local and widespread pain and hypersensitivity via Proto-oncogene tyrosine-protein kinase receptor (RET)-mediated upregulation of multiple downstream TRP receptors. In this proposal, we will use multiple OA models and clinically relevant outcome measures, and leverage our unique access to dogs with naturally occurring OA, to achieve the following aims: Aim 1: To test the hypothesis that ARTN expression is increased in OA and is responsible for pain. Aim 2: To test the hypothesis that ARTN/GFRα3 signaling is responsible for behaviorally manifested OA pain both in early and late stage disease. Aim 3: To test the hypothesis that RET-dependent ARTN/GFRα3 signaling results in changes in multiple TRP channel expression and activation. Aim 4: To test/validate involvement of the above-described key molecules in a naturally occurring large animal model of OA (dog). Overall, this will be the first work investigating the role and mechanisms of ARTN/GFRα3/TRP channel in OA pain and sensitivity. Based on solid, clinically relevant preliminary data, and leveraging PI expertise from two different and complementary disciplines, successful completion of this proposed work has the potential to identify clinically relevant neural mechanisms leading to the development of novel, effective therapeutics for the treatment of OA-pain in humans.

项目概要关节炎影响着近 6000 万美国成年人，并且发病率不断增加，其中骨关节炎 (OA) 是最常见的疾病最常见的关节炎是由关节组织退化引起的，并且与之相关。 OA 疼痛是社会上约 80% 的 OA 患者承受慢性疼痛的主要原因。行动受限，25% 无法进行主要的日常生活活动。仅限于类固醇注射、非类固醇抗炎药 (NSAIDS)、阿片类药物和非类固醇药物不幸的是，这些治疗方法都是药理学方法（运动、减肥）。由于持续的疼痛，有助于体重管理的运动对患者来说很困难。引起胃肠道刺激和出血，并增加心脏病发作或中风的风险，阿片类药物与成瘾和滥用有关（实际上会加剧慢性疼痛），显然，这是一个迫切的需要。为患有 OA 疼痛的患者确定新的治疗靶点和/或治疗方法。提出迄今为止未被认识的神经通路是 OA 疼痛的关键组成部分。 ARTN、其受体 GFRα3 和神经上的“疼痛”通道（瞬时受体电位 [TRP] 通道）。该通路的激活引发并维持 OA 疼痛中心假设（基于中的初步数据。多种物种（小鼠、狗、猫、人））是 OA 关节滑膜释放的 ARTN，以响应损伤，导致局部和远端感觉神经中的受体 GFRα3 从头增加，产生局部以及通过原癌基因酪氨酸蛋白激酶受体（RET）介导的广泛疼痛和过敏多个下游 TRP 受体的上调在本提案中，我们将使用多个 OA 模型和临床相关的结果测量，并利用我们对患有自然发生 OA 的狗的独特接触，实现以下目标：目标 1：检验 OA 中 ARTN 表达增加的假设目标 2：检验 ARTN/GFRα3 信号传导与行为有关的假设。目标 3：检验 RET 依赖性的假设。 ARTN/GFRα3 信号传导导致多个 TRP 通道表达和激活发生变化。目标 4：在自然发生的大型动物模型中测试/验证上述关键分子的参与 OA（狗）。总的来说，这将是第一个研究 ARTN/GFRα3/TRP 通道的作用和机制的工作。基于可靠的、临床相关的初步数据，并利用 PI 的专业知识。两个不同且互补的学科，成功完成这项拟议工作有可能确定临床相关的神经机制，从而开发出新的、有效的治疗方法治疗人类 OA 疼痛。